|Lai, Chao Qiang|
Submitted to: Nutrition Metabolism and Cardiovascular Disease
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/6/2009
Publication Date: 8/18/2009
Citation: Junyent, M., Tucker, K.L., Lane, J.M., Mattei, J., Smith, C., Parnell, L.D., Lai, C., Ordovas, J.M. 2009. The effect of ABCG5/G8 polymorphisms on plasma HDL cholesterol levels depends on the ABCA1 gene variation in the Boston Puerto Rican Health Study. Nutrition Metabolism and Cardiovascular Disease. 18:64-69. Interpretive Summary: The proteins ABCG5 and ABCG8 are each two halves of a transporter that functions to limit intestinal absorption and promote biliary excretion of sterols, such as cholesterol. Genetic variation in the two genes encoding these proteins has been lined to sterol accumulation, notably HDL-cholesterol ("good cholesterol") and atherosclerosis. An examination of the biochemical pathways involved in ABCG5/ABCG8 function and HDL levels underscores connections to a third protein, ABCA1. Thus, we sought to examine the effects of genetic variants in the three genes, ABCA1, ABCG5 and ABCG8, on HDL levels. The genetic variants were analyzed in 788 participants in the Boston Puerto Rican Health Study. Our results show that variants of ABCG8 and ABCA1 act in a cooperative manner. Specifically, persons with the less common version of one ABCG8 variant (5U145A>C) displayed lower HDL levels than persons with two copies on the more common version of this variant, only if they also harbored the less common version of two ABCA1 variants (i27943G>A, i48168G>A). Low HDL is an atherosclerosis risk factor. Another pair of ABCG8 and ABCA1 showed similar results. In conclusion, the interaction between ABCA1 and ABCG8 supports a strong role for ABCA1 in ABCG5/G8 action on sterol transport.
Technical Abstract: Background: ATP-binding cassette transporters G5/G8 have shown an association with HDL-C. One of the most likely mechanisms to explain those associations is through ABCA1. Objective: To assess whether the effect of ABCG5/G8 polymorphisms on HDL-C is dependent on ABCA1, we studied potential interactions between SNPs at ABCG5/G8 (i7892T>C, 5U145A>C, T54CA>G, T400KC>A) and ABCA1 (i27943G>A, i48168G>A, K219RG>A, i125970G>C, 3U8995A>G) with HDL-C. Results: ABCG5/G8 and ABCA1 SNPs were genotyped in 788 participants (228 men/ 560 women) in the Boston Puerto Rican Health Study. A significant gene-gene interaction for HDL-C was found. Minor allele carriers at SNP ABCG8_5U145A>C displayed lower HDL-C levels than homozygotes for the major allele, if they were carriers of minor alleles at ABCA1 (i27943G>A, i48168G>A) whereas a trend towards higher HDL-C was seen in homozygotes for the major allele at ABCG8 depending on ABCA1 genotypes (P for interaction=0.026 and 0.003, respectively). Significant interactions for HDL-C were also observed between ABCG8 (T54CA>G, T400KC>A) and ABCA1_i48168C>T SNPs (P=0.020 and P=0.012, respectively), in which carriers of minor alleles and homozygotes for the T400 allele at ABCG8 SNPs showed lower concentrations, only if they were carriers of the minor allele at ABCA1. Conclusions: This gene-gene interaction supports that the effect of ABCG5/G8 variants on HDL-C levels is dependent of ABCA1 expression.